Regular antibiotics for preventing pneumococcal infection in young children with sickle cell disease

Review question

We reviewed the evidence about the effects of prophylactic antibiotic regimens for preventing pneumococcal infection in children with sickle cell disease (SCD). This is an updated version of a previously published Cochrane Review.

Background

People living with SCD are especially prone to respiratory and blood infections. These infections are often caused by a germ (bacteria) known as Streptococcus pneumoniae, otherwise known as pneumococcus, which can cause many types of serious illnesses. Individuals with SCD can get infections more easily than unaffected persons because their spleen (organ that filters blood) does not work correctly, and also because damaged tissue and bone resulting from SCD can harbour bacteria. Infection prevention is therefore one of the major ways to improve the health of persons living with SCD and reduce the risk of death. The highest risk of infection occurs in children under three years old, but the special vaccines that help to prevent illnesses with Streptococcus pneumoniae are of limited use in this young population. Therefore, regular antibiotics in addition to these special vaccines are needed to prevent infection. As risk of infection decreases with age, there might be a time when preventative antibiotic treatment can be discontinued.

Search date

The evidence is current to 19 December 2016.

Study characteristics

We gathered evidence for this Cochrane Review by examining three clinical trials with over 800 children included.

Key results and quality of the evidence

All three clinical trials showed a reduced rate of pneumococcal infection in children with SCD receiving penicillin preventatively. Two of these trials looked at whether treatment was effective. The third trial followed on from one of the early trials and looked at when it was safe to stop treatment. Adverse drug effects were rare and minor. However, there were problems with children keeping to the treatment schedule and with the development of antibiotic resistance. The quality of the evidence for both primary and secondary outcomes (end result) was judged to be low.

We conclude that penicillin given preventatively reduces the rate of pneumococcal infections in children with SCD under five years of age. The risk of infection in older children is lower, and the follow-on trial did not show a significant increase in risk when regular penicillin was halted at five years old. Further research is needed to look at how commonly bacteria develop that are resistant to treatment and how clinically important this is.

Authors' conclusions: 

The evidence examined suggests that prophylactic penicillin significantly reduces risk of pneumococcal infection in children with homozygous SCD, and is associated with minimal adverse reactions. Further research may help to determine the ideal age to safely withdraw penicillin.

Read the full abstract...
Background: 

Persons with sickle cell disease (SCD) are particularly susceptible to infection. Infants and very young children are especially vulnerable. The 'Co-operative Study of Sickle Cell Disease' observed an incidence rate for pneumococcal septicaemia of 10 per 100 person years in children under the age of three years. Vaccines, including customary pneumococcal vaccines, may be of limited use in this age group. Therefore, prophylactic penicillin regimens may be advisable for this population. This is an update of a Cochrane Review first published in 2002, and previously updated, most recently in 2014.

Objectives: 

To assess the effects of antibiotic prophylaxis against pneumococcus in children with SCD in relation to:

1. incidence of infection;

2. mortality;

3. drug-related adverse events (as reported in the included studies) to the individual and the community;

4. the impact of discontinuing at various ages on incidence of infection and mortality.

Search strategy: 

We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Haemoglobinopathies Trials Register, which is comprised of references identified from comprehensive electronic database searches and also two clinical trials registries: ClinicalTrials.gov and the WHO International Registry Platform. Additionally, we carried out handsearching of relevant journals and abstract books of conference proceedings.

Date of the most recent search: 19 December 2016.

Selection criteria: 

All randomised or quasi-randomised controlled trials comparing prophylactic antibiotics to prevent pneumococcal infection in children with SCD with placebo, no treatment or a comparator drug.

Data collection and analysis: 

Both authors independently extracted data and assessed trial quality. The authors used the GRADE criteria to assess the quality of the evidence.

Main results: 

Five trials were identified by the searches, of which three trials (880 children randomised) met the inclusion criteria. All of the included trials showed a reduced incidence of infection in children with SCD (SS or Sβ0Thal) receiving prophylactic penicillin. In trials which investigated initiation of penicillin on risk of pneumococcal infection, the odds ratio was 0.37 (95% confidence interval 0.16 to 0.86) (two trials, 457 children) (low-quality evidence), while for withdrawal the odds ratio was 0.49 (95% confidence interval 0.09 to 2.71) (one trial, 400 children) (low-quality evidence). Adverse drug effects were rare and minor. Rates of pneumococcal infection were found to be relatively low in children over the age of five.

Overall, the quality of the evidence for all outcomes was judged to be low. The results from the risk of bias assessment undertaken identified two domains in which the risk of bias was considered to be high, these were incomplete outcome data (attrition bias) (two trials) and allocation concealment (selection bias) (one trial). Domains considered to have a low risk of bias for all three trials were selective reporting (reporting bias) and blinding (performance and detection bias).

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